Fishing for Parkinson’s research

Singapore scientists’ zebrafish model for Parkinson’s disease an important step closer to drug development for the disease

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SINGAPORE—A zebrafish model has been developed by scientists at the Genome Institute of Singapore (GIS), a biomedical research institute of the Agency for Science, Technology and Research (A*STAR), to facilitate the study of Parkinson's Disease (PD), with the aim of using the model to better understand the mechanism attached to the disease's development.

Researchers expect that the results and knowledge gathered will be helpful to screen for drugs that could be useful in treating the condition. The recent study portrays the zebrafish model for LRRK2 mutation-related PD and it confirms that the new model has successfully been able to conquer the problems faced by the previous models.

The research team, which was lead by Dr. Liu Jianjun, closely analyzed the genes in zebrafish by obstructing its standard function, and the findings were published in PLoS Genetics on April 22. According to Jianjun, the team's work has demonstrated zebrafish as a suitable model for PD study.

"Due to the several advantages of zebrafish model—for example, they are easy to maintain and breed, have rapid development and are transparent—our zebrafish PD model could be utilized for the large-scale drug screening for PD in the future," Jianjun points out.

"This work shows how the use of a simple model system in fish can help decipher the  root causes of a serious human disorder like Parkinson's disease," adds Edison Liu, executive director of the GIS.

Jianjun points out that the key finding of the research is that the mutation of LRRK2 can have causal PD-like neurodegeneration and locomotive defects.

"The neurodegenerative and locomotive defects can be rescued by expressing human LRRK2," Jianjun says. "Furthermore, the locomotive defect observed in the mutant zebrafish can be rescued by administration of Levo-dopa, a compound currently used for treating PD patients. This makes it a good animal model for PD disease."

Parkinson's disease (PD) is a degenerative disease of the brain that often impairs motor skills, speech and other functions. The discovery of several gene mutations in affected patients clearly demonstrated the involvement of genetic factors in the development of PD. LRRK2 was discovered from previous studies by the same team of researchers to be one of the most important genetic causes of PD in the Asian population.  
"This novel and elegant study has illuminated the role of an otherwise poorly understood but important domain of LRRK2 that is associated with an increased risk for Parkinson's disease amongst Asian populations," says Dr. Lim Kah Leong, associate professor of the National Neuroscience Institute and Duke-NUS Graduate Medical School. "The use of zebrafish as a disease model is a clever approach. I  am definitely pleased to note that our arsenal of experimental organisms for drug screening has expanded with this study."  
The zebrafish model derived from this study serves as a vertebrate model suitable for  large-scale drug screening and provides a good disease model for PD. Using a novel technology known as the Zinc-finger nucleases (ZFNs), further research is being carried out to generate additional mutations of zebrafish LRRK2 gene. Such mutated fish can be used for advancing investigation for the biological mechanism of PD and screening of new drugs for PD treatment.
Jianjun notes that in the current study, the truncation of LRRK2 protein and thus the neurodegenerative defects in zebrafish is generated by using some transient knockdown techniques, which is not suitable for deep biological investigation and large-scale drug screening.

"We are therefore working to use Zinc Finger Nuclease (ZFN) technology to generate stable mutant zebrafish lines of LRRK2 to pursue further studies," Jianjun says. "The next stage of this research should generate a stable mutant zebrafish lines which can be used for large-scale drug screening and in-depth PD mechanism study."

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